The proposed research will examine the significance of Sonic hedgehog (Shh) signaling during postnatal development of the penis and will examine the potential regulation of Shh by testosterone. Shh is a secreted glycopeptide that is critically important to mesenchymal-epithelial interactions between tissue layers during embryogenesis. A significant function for Shh in postnatal development has only recently been identified in an organ that undergoes considerable postnatal morphogenesis, the prostate (Podlasek et al., 1999a). Thus Shh function is not restricted to the embryonic period and in organs that undergo extensive postnatal differentiation, Shh activity may be substantial. Like the prostate, development in the penis is primarily a postnatal event, with extensive development taking place after birth. We will present preliminary evidence in the adult that establishes Shh to be absolutely essential for maintaining penile homeostasis. This is significant since diabetic rats exhibit profoundly altered Shh signaling. This same rat model (BB/WOR) has a high incidence of erectile dysfunction (McVary et al., 1997). Thus there is evidence to suggest a potential link between disrupted Shh signaling and the physiological abnormality of erectile dysfunction. Diabetic impotence is a devastating pathologic development that affects 10-30 million American men, and costs in excess of $150 million for inpatient urologic care alone (1985 dollars). As individuals live longer there is a greater concern for quality of life and treatment options for individuals with erectile dysfunction are only partially effective (Vale et al., 2000). A better understanding of how penile morphology is established and maintained in the juvenile would significantly enhance the potential for improved treatment. The proposed experiments are ideally suited to satisfy the goals of this RFA since innovative technology is used to identify novel signaling molecules involved in urologic tissue development and altered regulation of this molecule is prominent in urologic complications of diabetes. The power of this proposal is its potential to provide novel and critically important insight into the mechanism of diabetes induced erectile dysfunction.